F. M. Singer et al., "New Inhibitors of in vitro Conversion of Acetate and Mevalonate to Cholesterol", Proc. Soc. Exper. Biol. Med., 102, 370 (1959) and F. H. Hulcher, "Inhibition of Hepatic Cholesterol Biosynthesis by 3,5-Dihydroxy-3,4,4,-trimethylvaleric Acid and its Site of Action," Arch. Biochem. Biophys., 146, 422 (1971) disclose that certain mevalonate derivatives inhibit the biosynthesis of cholesterol.
Singer et al. reported that fluoromevalonic acid is more effective in inhibiting biosynthesis of cholesterol (as measured by in vitro conversion of labeled acetate and labeled mevalonate into cholesterol) than .DELTA.4-androstene-17.alpha.-ol-3-one-17.beta.-oic acid and .DELTA.1-testololactone.
Hulcher reported that an analog of mevalonic acid, namely, 3,5-dihydroxy-3,4,4-trimethylvaleric acid strongly inhibits cholesterol biosynthesis by rat liver homogenates.
U.S. Pat. No. 3,983,140 to Endo et al. discloses the fermentation product ML-236B referred to generically as compactin ##STR4## (also referred to as mevastatin) which is prepared by cultivation of a microorganism of the genus Penicillium. This fermentation process is disclosed in U.S. Pat. No. 4,049,495 issued Sep. 20, 1977 to Endo et al.
Brown, A. G., et al., (Beecham Pharmaceuticals Research Div.), "Crystal and Molecular Structure of Compactin, a New Antifungal Metabolite from Penicillium Brevicompactum", J. Chem. Soc. Perkin I. 1165-1170 (1976) confirms that compactin has a complex mevalonolactone structure as disclosed by Endo et al. in the above patents.
U.S. Pat. No. 4,231,938 to Monaghan et al. discloses mevinolin (lovastatin, Monacolin K) ##STR5## (also referred to as MK-803) which is prepared by culturing a microorganism of the genus Aspergillus.
U.S. Pat. No. 4,346,227 to Terahara et al discloses pravastatin ##STR6##
Pravastatin is prepared by the enzymatic hydroxylation of compactin or its carboxylic acid as disclosed in U.S. Pat. No. 4,410,629 to Terahara et al.
U.S. Pat. No. 4,448,979 issued May 15, 1984 to Terahara et al discloses the lactone of pravastatin.
U.S. Pat. Nos. 4,444,784 and 4,450,171 to Hoffman et al disclose various antihypercholesterolemic compounds including synvinolin (simvastatin) ##STR7## as well as compounds of the structures ##STR8## wherein R.sup.1 is H or CH.sub.3, R can be an alkyl group including ##STR9## X, Y and Z are single and/or double bonds in all possible combinations.
European Patent Application 0065835A1 filed by Sankyo discloses cholesterol biosynthesis inhibiting compounds of the structure ##STR10## and their corresponding free carboxylic acids, which may be represented by the following formula ##STR11## (in which one of R.sup.1 and R.sup.2 represents a hydrogen atom and the other represents a hydroxy group), and salts and esters of the carboxylic acids.
European Patent Application 0142146A2 filed by Merck discloses mevinolin-like compounds of the structure ##STR12## wherein
R.sup.1 is
1) hydrogen, PA1 2) C.sub.1-4 alkyl, PA1 3) 2,3-dihydroxypropyl, PA1 4) alkali metal cation, such as Na.sup.+, or K.sup.+, or PA1 5) ammonium of formula N.sup.+ R.sup.3 R.sup.4 R.sup.5 R.sup.6 wherein R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are independently hydrogen or C.sub.1-4 alkyl or two of R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are joined together to form a 5 or 6-membered heterocycle such as pyrrolidino or piperidino with the nitrogen to which they are attached;
E is --CH.sub.2 CH.sub.2 --, --CH.dbd.CH--, or --(CH.sub.2).sub.3 --; and Z is ##STR13## wherein the dotted lines represent all of the possible oxidation states of the bicyclic system such as naphthalene, dihydro-, tetrahydro-, hexahydro-, octahydro-, and decahydronaphthalene;
X is --O-- or NR.sup.9 wherein
R.sup.9 is H or C.sub.1-3 alkyl;
R.sup.7 is C.sub.2-8 alkyl; and
R.sup.8 is H or --CH.sub.3 ; ##STR14## wherein R.sup.10, R.sup.11 and R.sup.12 are independently
a) hydrogen,
b) halogen, such as bromo, chloro or fluoro,
c) C.sub.1-4 alkyl,
d) halo-C.sub.1-4 alkyl,
e) phenyl either unsubstituted or substituted with one or more of
i) C.sub.1-4 alkyl,
ii) C.sub.1-4 alkyl,
iii) C.sub.2-8 alkanoyloxy, or
iv) halo-C.sub.1-4 alkyl,
v) halo, such as bromo, chloro or fluoro,
f) OR.sup.13 wherein R.sup.13 is
i) hydrogen,
ii) C.sub.1-8 alkanoyl,
iii) benzoyl,
iv) phenyl,
v) halophenyl,
vi) phenyl-C.sub.1-3 alkyl, either unsubstituted or substituted with one or more halogen, C.sub.1-4 alkoxy, C.sub.1-4 alkyl or halo-C.sub.1-4 alkyl,
vii) C.sub.1-9 alkyl,
viii) cinnamyl,
ix) halo-C.sub.1-4 alkyl,
x) allyl,
xi) C.sub.3-6 cycloalkyl-C.sub.1-3 alkyl,
Xii) adamantyl-C.sub.1-3 alkyl, ##STR15## wherein n is 0-2, and is halo such as chloro, bromo or fluoro, or C.sub.1-4 alkyl, and ##STR16## wherein the dotted lines represent possible double bonds there being 0, 1 or 2 double bonds; m represents 1, 2 or 3; and
R.sup.15 is
1) methyl,
2) hydroxy,
3) C.sub.1-4 alkoxy,
4) oxo or
5) halo.
European Patent Application EP283,217 (Merck Co., Inc.) relates to the preparation of 6-aryl- or arylalkyl-3,4,5,6-tetrahydropyran-2-one derivatives useful as antihypercholesterolemics which have the formula ##STR17## wherein Z is phenyl, naphthyl, thiophenyl or thiazyl which may be substituted with Cl, F, OH, alkyl, alkoxy, alkanoyloxy, alkanoylamino, alkoxycarbonyl, phenyl, hydroxyalkyl, trifluoromethylalkanoylamino; ##STR18## wherein E is a bond, CH.sub.2, (CH.sub.2).sub.2 ; R.sub.1, R.sub.2 and R.sub.3 are H, Cl, F, (Cl-, F- or alkanoyloxy-substituted)slkyl, (Cl- or F-substituted)phenyl, alkoxy, alkanoyloxy, OH, phenoxy) and their derivatives; and R.sub.5 is H or alkyl.